EP4320117A2 - Neue hepatoselektive polyadenylierende polymerasen-hemmer und verfahren zu ihrer verwendung - Google Patents

Neue hepatoselektive polyadenylierende polymerasen-hemmer und verfahren zu ihrer verwendung

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Publication number
EP4320117A2
EP4320117A2 EP22785197.9A EP22785197A EP4320117A2 EP 4320117 A2 EP4320117 A2 EP 4320117A2 EP 22785197 A EP22785197 A EP 22785197A EP 4320117 A2 EP4320117 A2 EP 4320117A2
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EP
European Patent Office
Prior art keywords
compound
formula
alkyl
optionally
group
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EP22785197.9A
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English (en)
French (fr)
Inventor
Yanming Du
Timothy M. Block
Tianlun ZHOU
Nicky HWANG
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Baruch S Blumberg Institute
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Baruch S Blumberg Institute
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Publication of EP4320117A2 publication Critical patent/EP4320117A2/de
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/10—Aza-phenanthrenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention describes compounds and methods useful as hepatoselective Polyadenylating Polymerases 5 and 7 (PAPD 5 & 7) inhibitors, useful for the treatment of hepatitis B and related conditions.
  • PAPD 5 & 7 hepatoselective Polyadenylating Polymerases 5 and 7
  • the present invention further describes a novel chemotype useful for the treatment of liver cancer and other diseases that involve Polyadenylating Polymerases 5 and 7 activity.
  • HBV hepatitis B virus
  • HCC hepatocellular carcinoma
  • Reduction of HBsAg antigenemia (HBsAg in the blood) has become one of the three goals for a primary end point of CHB therapy along with reduction of viremia and normalization of blood level liver derived transaminases.
  • HBsAg in addition to being a protein essential to complete the viral life cycle, is also believed to play a role in immunosuppression and maintenance of the chronic infected state.
  • current standard of care medications with either pegylated interferon alpha or nucleos(t)ide analogues (NUCs) can suppress viral replication, none reliably induce the loss of HBsAg. There is thus a significant need to develop new HBV therapeutics.
  • DHQ dihydroquinolizinone
  • RG-7834 DHQ-1
  • HBV infected uPA-SCID mice harboring human hepatocytes resulted in 1 log reduction of HBsAg in the circulation.
  • WHV woodchuck hepatitis virus
  • PAPD 5 & 7 are non canonical polyadenylating polymerases that mediate short adenylations and provide a signal for the degradation of aberrant cell transcripts and maturation of a subset of non coding transcripts.
  • PAPD5 & 7 inhibition is the basis of its anti-HBV activity. That inhibition of PAPD5 and, or 7, with DHQ-1 causes a reduction in HBV RNA levels suggests that HBV mRNA behaves very differently than does most host mRNA. This provides a novel opportunity for antiviral drug development.
  • the present invention is directed toward novel hepatoselective inhibitors of PAPD 5 and 7, compounds of formula (I),
  • Z 1 is selected from the group consisting of N and CR 1 ;
  • Z 2 is selected from the group consisting of N and CR 4 ;
  • Z 1 and Z 2 are not N at the same time;
  • X 3 is selected from the group consisting of CH 2 R, -OR, -NR 3 R and X 4 is selected from the group consisting of CHR 5 , O, S, SO, and SO 2 ;
  • X 5 is selected from the group consisting of N and C;
  • X 6 is selected from the group consisting of CR 7 and NR 7 ;
  • X 4 is selected from the group consisting of O, S, SO, and SO 2 ;
  • n 1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;
  • n 2 is 2, 3, 4, 5, 6, 7, or 8;
  • n 3 is 1, 2, 3, 4, 5, 6, 7, or 8;
  • n 4 is 1, 2, 3, 4, 5, 6, or 7;
  • n 5 is 1, 2, 3, 4, 5, 6, or 7;
  • n 6 is 1, 2, 3, 4, 5, 6, or 7;
  • n 7 is 1, 2, 3, 4, 5, 6, or 7;
  • n 8 is 1, 2, 3, 4, 5, 6, or 7;
  • n 9 is 0, 1, 2, 3, 4, 5, 6, or 7;
  • n 2 and n 3 do not exceed 14:
  • n 4 and n 5 do not exceed 14:
  • n 6 and n 7 do not exceed 14:
  • n 8 and n 9 does not exceed 14: m 1 is 1,2 or 3; m 2 is 0, 1, 2, or 3;
  • R 1 is selected from the group consisting of H, halogen, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3 - 7 branched alkyl, and C 3-7 cycloalkyl;
  • R 1a is at each occurrence independently selected from the group hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl
  • R lb is at each occurrence independently selected from the group hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl
  • R 1c is at each occurrence independently selected from the group hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl;
  • R ld is at each occurrence independently selected from the group hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl;
  • R le is at each occurrence independently selected from the group hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl;
  • R lf is at each occurrence independently selected from the group hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl;
  • R 2 is selected from the group consisting of H, halogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 3-7 branched alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 branched alkoxy, CN, and aromatic ring with 0-3 heteroatoms;
  • R 1 and R 2 are taken together with the atoms to which they are bound to form a 5-7 membered ring that contains 0-2 heteroatoms;
  • R 3 is selected from group consisting of hydrogen, C 1-6 alkyl, and C2-6 alkene
  • R 4 is selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 alkoxy, and CN;
  • R 3 and R 4 are taken together to with the atoms to which they are bound to form a 5-7 membered ring with 0-2 heteroatoms;
  • R 3 and R 4 are taken together to with the atoms to which they are bound to form a 5-6 membered aromatic ring with 0-2 heteroatoms;
  • R 5 is selected from the group consisting of H, C 1-6 alkyl, and C 3-7 branch alkyl;
  • R 6 is selected from the group consisting of H, C 1-10 alkyl, C 1-10 haloalkyl, C 3-7 branched alkyl, C 3-7 cycloalkyl, and optionally substituted aryl;
  • R 5 and R 6 are taken together to with the atoms to which they are bound to form a 5-7 membered ring;
  • R 7 is selected from the group consisting of H, halogen, C 1-6 alkyl, C 3- 7 cycloalkyl, C 3-7 branched alkyl, and CN;
  • R 7 is selected from the group consisting of H, C 1-6 alkyl, C 3-7 cycloalkyl, and C 3-7 branched alkyl;
  • R 8 is selected from the group consisting of is H and C 1-6 alkyl.
  • the present invention further relates to compositions comprising: an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention also relates to a method for treating or preventing diseases that involve PAPD 5 and 7, including, for example, hepatitis B, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention yet further relates to a method for treating or preventing diseases that involve PAPD 5 and 7, including, for example, hepatitis B, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention also relates to a method for treating or preventing disease or conditions associated with hepatitis B, and diseases that involve PAPD 5 and 7. Said methods comprise administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention yet further relates to a method for treating or preventing disease or conditions associated with hepatitis B, and diseases that involve PAPD 5 and 7, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention also relates to a method for treating or preventing disease or conditions associated with PAPD 5 and 7. Said methods comprise administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention yet further relates to a method for treating or preventing disease or conditions associated with PAPD 5 and 7, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention further relates to a process for preparing the hepatoselective PAPD 5 and 7 inhibitors of the present invention.
  • Figure 1 depicts a mean plasma concentration vs time profile for 65042-E-OH (Example 6) after 3 mg/kg IV and 8 mg/kg PO in CD1 Mice.
  • Figure 2 depicts a mean plasma and liver concentration vs time profile for 65042-E-OH (Example 6) after 8 mg/kg PO in CD1 Mice.
  • the hepatoseletive inhibitors of PAPD 5 and 7 agents of the present invention are capable of treating and preventing diseases associated with hepatitis B virus surface antigen, for example hepatitis B. It has been discovered that compounds of the disclosure are inhibitors of PAPD 5 and 7. In addition, it has been determined that compounds of the disclosure are substrates for organic anion transporting poly-peptide protein 1B1 (OATP1B1) and organic anion transporting poly-peptide protein 1B3 (OATP1B3), a feature not seen in related compounds such as DHQ-1. It has further been determined that the ability of compounds of the disclosure to act as substrates of a OATP1B1 and OATP1B3 leads to unexpected, preferential concentration of compound in the liver in comparison to the systemic circulation.
  • OATP1B1 organic anion transporting poly-peptide protein 1B1
  • OATP1B3 organic anion transporting poly-peptide protein 1B3
  • compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps.
  • halogen shall mean chlorine, bromine, fluorine and iodine.
  • alkyl and/or “aliphatic” whether used alone or as part of a substituent group refers to straight and branched carbon chains having 1 to 20 carbon atoms or any number within this range, for example 1 to 6 carbon atoms or 1 to 4 carbon atoms.
  • Designated numbers of carbon atoms e.g. C 1-6 ) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent.
  • alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like.
  • Alkyl groups can be optionally substituted.
  • substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2- hydroxyethyl, 1,2-difluoroethyl, 3-carboxypropyl, and the like.
  • substituent groups with multiple alkyl groups such as (C 1-6 alkyl)2amino, the alkyl groups may be the same or different.
  • alkenyl and alkynyl groups refer to straight and branched carbon chains having 2 or more carbon atoms, preferably 2 to 20, wherein an alkenyl chain has at least one double bond in the chain and an alkynyl chain has at least one triple bond in the chain.
  • Alkenyl and alkynyl groups can be optionally substituted.
  • Nonlimiting examples of alkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also 2-methylethenyl), isopropenyl (also 2- methylethen-2-yl), buten-4-yl, and the like.
  • Nonlimiting examples of substituted alkenyl groups include 2-chloroethenyl (also 2-chlorovinyl), 4-hydroxybuten-1-yl, 7-hydroxy-7- methyloct-4-en-2-yl, 7-hydroxy-7-methyloct-3,5-dien-2-yl, and the like.
  • Nonlimiting examples of alkynyl groups include ethynyl, prop-2-ynyl (also propargyl), propyn-1-yl, and 2-methyl-hex-4-yn-1-yl.
  • Nonlimiting examples of substituted alkynyl groups include, 5- hydroxy-5-methylhex-3-ynyl, 6-hydroxy-6-methylhept-3-yn-2-yl, 5-hydroxy-5-ethylhept-3- ynyl, and the like.
  • cycloalkyl refers to a non-aromatic carbon-containing ring including cyclized alkyl, alkenyl, and alkynyl groups, e.g., having from 3 to 14 ring carbon atoms, preferably from 3 to 7 or 3 to 6 ring carbon atoms, or even 3 to 4 ring carbon atoms, and optionally containing one or more (e.g., 1, 2, or 3) double or triple bond.
  • Cycloalkyl groups can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure. Cycloalkyl rings can be optionally substituted.
  • Nonlimiting examples of cycloalkyl groups include: cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4- hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl, octahydro- 1H- indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl; bicyclo[6.2.0]decany
  • cycloalkyl also includes carbocyclic rings which are bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3- dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.
  • “Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen.
  • Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an alkyl group have been replaced with halogens (e.g., -CF 3 , -CF 2 CF 3 ). Haloalkyl groups can optionally be substituted with one or more substituents in addition to halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.
  • alkoxy refers to the group -O-alkyl, wherein the alkyl group is as defined above. Alkoxy groups optionally may be substituted.
  • C 3 -C 6 cyclic alkoxy refers to a ring containing 3 to 6 carbon atoms and at least one oxygen atom (e.g., tetrahydrofuran, tetrahydro-2H-pyran). C 3 -C 6 cyclic alkoxy groups optionally may be substituted.
  • Haloalkoxy refers to the group -O-alkyl, wherein the alkyl group is as defined above wherein the -O-alkyl is substituted with 1 or more halogen.
  • Haloalkoxy groups include perhaloalkyl groups, wherein all hydrogens of an alkoxy group have been replaced with halogens (e.g., -OCF 3 , -OCF 2 CF 3 ).
  • Haloalkoxy groups can optionally be substituted with one or more substituents in addition to halogen.
  • haloalkoxy groups include, but are not limited to, fluoromethoxy, dichloroethoxy, trifluoromethoxy, trichloromethoxy, pentafluoroethoxy, and pentachloroethoxy groups.
  • aryl wherein used alone or as part of another group, is defined herein as a an unsaturated, aromatic monocyclic ring of 6 carbon members or to an unsaturated, aromatic polycyclic ring of from 10 to 14 carbon members.
  • Aryl rings can be, for example, phenyl or naphthyl ring each optionally substituted with one or more moieties capable of replacing one or more hydrogen atoms.
  • Non-limiting examples of aryl groups include: phenyl, naphthylen-1-yl, naphthylen-2-yl, 4-fluorophenyl, 2-hydroxyphenyl, 3- methylphenyl, 2-amino-4-fluorophenyl, 2-(N,N-diethylamino)phenyl, 2-cyanophenyl, 2,6-di- tert-butylphenyl, 3-methoxyphenyl, 8-hydroxynaphthylen-2-yl 4,5-dimethoxynaphthylen-1- yl, and 6-cyano-naphthylen-1-yl.
  • Aryl groups also include, for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings.
  • phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings.
  • arylalkyl refers to the group -alkyl-aryl, where the alkyl and aryl groups are as defined herein.
  • Aralkyl groups of the present invention are optionally substituted. Examples of arylalkyl groups include, for example, benzyl, 1- phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl and the like.
  • heterocyclic and/or “heterocycle” and/or “heterocylyl,” whether used alone or as part of another group, are defined herein as one or more ring having from 3 to 20 atoms wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and wherein further the ring that includes the heteroatom is non-aromatic.
  • the non-heteroatom bearing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl).
  • heterocycle groups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S).
  • N nitrogen
  • O oxygen
  • S sulfur
  • One or more N or S atoms in a heterocycle group can be oxidized.
  • Heterocycle groups can be optionally substituted.
  • Non-limiting examples of heterocyclic units having a single ring include: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2, 3,4,5- tetrahydro- 1H-azcpinyl, 2,3-dihydro- 1H-indole, and 1,2,3,4
  • Non- limiting examples of heterocyclic units having 2 or more rings include: hcxahydro- 1H- pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hcxahydro- 1H- indolyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro- 1H-cycloocta[b]pyrrolyl.
  • heteroaryl whether used alone or as part of another group, is defined herein as one or more rings having from 5 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O), or sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic.
  • the non-heteroatom bearing ring may be a carbocycle (e.g., 6,7-Dihydro-5H- cyclopcntapyrimidine) or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl).
  • heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heteroaryl group can be oxidized. Heteroaryl groups can be substituted.
  • heteroaryl rings containing a single ring include: 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1 H- imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3- methylpyridinyl, and 4-dimethylaminopyridinyl.
  • heteroaryl rings containing 2 or more fused rings include: benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9/H- purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H- pyrro 1 o [ 2,3-d] pyrimidinyl, pyri do [ 2,3-d] pyrimidinyl, 2-phenylbenzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H- indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl, and isoquinol
  • heteroaryl group as described above is C 1 -C 5 heteroaryl, which has 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), or sulfur (S).
  • N nitrogen
  • O oxygen
  • S sulfur
  • C 1 -C 5 heteroaryl examples include, but are not limited to, triazinyl, thiazol-2-yl, thiazol-4-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.
  • the ring when two substituents are taken together to form a ring having a specified number of ring atoms (e.g., R 2 and R 3 taken together with the nitrogen (N) to which they are attached to form a ring having from 3 to 7 ring members), the ring can have carbon atoms and optionally one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S).
  • the ring can be saturated or partially saturated and can be optionally substituted.
  • fused ring units, as well as spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring.
  • 1,2,3,4-tetrahydroquinoline having the formula: is, for the purposes of the present invention, considered a heterocyclic unit.
  • 6,7-Dihydro-5N- cyclopentapyrimidine having the formula: is, for the purposes of the present invention, considered a heteroaryl unit.
  • the aryl ring will predominate and determine the type of category to which the ring is assigned.
  • 1, 2,3,4- tetrahydro-[l,8]naphthyridine having the formula: is, for the purposes of the present invention, considered a heteroaryl unit.
  • substituted is used throughout the specification.
  • the term “substituted” is defined herein as a moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several (e.g., 1 to 10) substituents as defined herein below.
  • the substituents are capable of replacing one or two hydrogen atoms of a single moiety at a time.
  • these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety or unit.
  • a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like.
  • a two hydrogen atom replacement includes carbonyl, oximino, and the like.
  • a two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like.
  • substituted is used throughout the present specification to indicate that a moiety can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as “substituted” any number of the hydrogen atoms may be replaced.
  • difluoromethyl is a substituted C 1 alkyl
  • trifluoromethyl is a substituted C 1 alkyl
  • 4- hydroxyphenyl is a substituted aromatic ring
  • (N,N-dimethyl-5-amino)octanyl is a substituted C 8 alkyl
  • 3-guanidinopropyl is a substituted C 3 alkyl
  • 2-carboxypyridinyl is a substituted heteroaryl.
  • variable groups defined herein e.g., alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryloxy, aryl, heterocycle and heteroaryl groups defined herein, whether used alone or as part of another group, can be optionally substituted. Optionally substituted groups will be so indicated.
  • the substituents are selected from i) -OR 11 ; for example, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 ; ii) -C(O)R 11 ; for example, -COCH 3 , -COCH 2 CH 3 , -C OCH 2 CH 2 CH 3 ; iii) -C(O)OR 11 ; for example, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -CO 2 CH 2 CH 2 CH 3 ; iv) -C(O)N(R 11 ) 2 ; for example, -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 ; v) -N(R 11 ) 2 ; for example, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NH(CH 2 CH 3 ); vi) hal
  • each R 11 is independently hydrogen, optionally substituted C 1 -C 6 linear or branched alkyl (e.g., optionally substituted C 1 -C 4 linear or branched alkyl), or optionally substituted C 3 -C 6 cycloalkyl (e.g optionally substituted C 3 -C 4 cycloalkyl); or two R 11 units can be taken together to form a ring comprising 3-7 ring atoms.
  • each R 11 is independently hydrogen, C 1 -C 6 linear or branched alkyl optionally substituted with halogen or C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl.
  • C 1-6 alkyl is specifically intended to individually disclose C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 , alkyl.
  • the terms “compound,” “analog,” and “composition of matter” stand equally well for the hepatoselective Polyadenylating Polymerases 5 and 7 (PAPD 5 & 7) inhibitors described herein, including all enantiomeric forms, diastereomeric forms, salts, and the like, and the terms “compound,” “analog,” and “composition of matter” are used interchangeably throughout the present specification.
  • PAPD 5 & 7 hepatoselective Polyadenylating Polymerases 5 and 7
  • Compounds described herein can contain an asymmetric atom (also referred as a chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers.
  • enantiomers optical isomers
  • diastereomers include such enantiomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
  • Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, which include, but are not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis.
  • the present teachings also encompass cis and trans isomers of compounds containing alkenyl moieties (e.g., alkenes and imines). It is also understood that the present teachings encompass all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography.
  • compositions of the present teachings which can have an acidic moiety, can be formed using organic and inorganic bases. Both mono and polyanionic salts are contemplated, depending on the number of acidic hydrogens available for deprotonation.
  • Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e.g., ethyl-tert- butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g., mono-, di- or triethanolamine).
  • metal salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts
  • ammonia salts and organic amine salts such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-,
  • inorganic bases include NaHCO 3 , Na 2 CO 3 , KHCO 3 , K 2 CO 3 , CS 2 CO 3 , LiOH, NaOH, KOH, NaH 2 PO 4 , Na 2 HPO 4 , and Na 3 PO 4 .
  • Internal salts also can be formed.
  • salts can be formed using organic and inorganic acids.
  • salts can be formed from the following acids: acetic, propionic, lactic, benzenesulfonic, benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well as other known pharmaceutically acceptable acids.
  • any variable occurs more than one time in any constituent or in any formula, its definition in each occurrence is independent of its definition at every other occurrence (e.g., in N(R 10 ) 2 , each R 10 may be the same or different than the other). Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • treat and “treating” and “treatment” as used herein, refer to partially or completely alleviating, inhibiting, ameliorating and/or relieving a condition from which a patient is suspected to suffer.
  • terapéuticaally effective and “effective dose” refer to a substance or an amount that elicits a desirable biological activity or effect.
  • the terms “subject” or “patient” are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals. Accordingly, the term “subject” or “patient” as used herein means any mammalian patient or subject to which the compounds of the invention can be administered.
  • accepted screening methods are employed to determine risk factors associated with a targeted or suspected disease or condition or to determine the status of an existing disease or condition in a subject. These screening methods include, for example, conventional work-ups to determine risk factors that may be associated with the targeted or suspected disease or condition. These and other routine methods allow the clinician to select patients in need of therapy using the methods and compounds of the present invention.
  • the hepatoselective Polyadenylating Polymerases 5 and 7 inhibitors are functionalized pyridin-4(1H)-ones, and include all enantiomeric and diastereomeric forms and pharmaceutically accepted salts thereof having the formula (I):
  • Z 1 is selected from the group consisting of N and CR 1 ;
  • Z 2 is selected from the group consisting of N and CR 4 ;
  • Z 1 and Z 2 are not N at the same time;
  • X 3 is selected from the group consisting of CHR 5 , -OR, -NR 3 R and X 4 is selected from the group consisting of CHR 5 , O, S, SO, and SO 2 ; X 5 is selected from the group consisting of N and C;
  • X 6 is selected from the group consisting of CR 7 and NR 7 ;
  • X 4 is selected from the group consisting of O, S, SO, and SO 2 ; n 1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; n 2 is 2, 3, 4, 5, 6, 7, or 8; n 3 is 1, 2, 3, 4, 5, 6, 7, or 8; n 4 is 1, 2, 3, 4, 5, 6, or 7; n 5 is 1, 2, 3, 4, 5, 6, or 7; n 6 is 1, 2, 3, 4, 5, 6, or 7; n 7 is 1, 2, 3, 4, 5, 6, or 7; n 8 is 1, 2, 3, 4, 5, 6, or 7; n 9 is 0, 1, 2, 3, 4, 5, 6, or 7;
  • n 2 and n 3 do not exceed 14:
  • n 4 and n 5 does not exceed 14:
  • n 6 and n 7 do not exceed 14:
  • n 8 and n 9 does not exceed 14: m 1 is 1, 2, or 3; m 2 is 0, 1, 2, or 3;
  • R 1 is selected from the group consisting of H, halogen, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3- 7 branched alkyl, and C 3-7 cycloalkyl;
  • R 1a is at each occurrence independently selected from the group hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl;
  • R 1b is at each occurrence independently selected from the group hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl;
  • R 1c is at each occurrence independently selected from the group hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl;
  • R 1d is at each occurrence independently selected from the group hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl;
  • R 1e is at each occurrence independently selected from the group hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl;
  • R 1f is at each occurrence independently selected from the group hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl;
  • R 2 is selected from the group consisting of H, halogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 3-7 branched alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 branched alkoxy, CN, and aromatic ring with 0-3 heteroatoms;
  • R 1 and R 2 are taken together to with the atoms to which they are bound to form a 5-7 membered ring that contains 0-2 heteroatoms;
  • R 3 is selected from group consisting of hydrogen, C 1-6 alkyl, and C 2-6 alkene
  • R 4 is selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 alkoxy, and CN;
  • R 3 and R 4 are taken together with the atoms to which they are bound to form a 5-7 membered ring with 0-2 heteroatoms;
  • R 3 and R 4 are taken together to with the atoms to which they are bound to form a 5-6 membered aromatic ring with 0-2 heteroatoms;
  • R 5 is selected from the group consisting of H,C 1-6 alkyl, and C 3-7 branch alkyl;
  • R 6 is selected from the group consisting of H, C 1-10 alkyl C 1-10 haloalkyl, C 3-7 branched alkyl, C 3-7 cycloalkyl, and optionally substituted aryl;
  • R 5 and R 6 are taken together to with the atoms to which they are bound to form a 5-7 membered ring;
  • R 7 is selected from the group consisting of H, halogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 branched alkyl, and CN;
  • R 7 is selected from the group consisting of H, C 1-6 alkyl, C 3-7 cycloalkyl, and C 3-7 branched alkyl;
  • R 8 is selected from the group consisting of is H and C 1-6 alkyl
  • the compounds of the present invention include compounds having formula (II):
  • the compounds of the present invention include compounds having formula (III):
  • the compounds of the present invention include compounds having formula (IV):
  • the compounds of the present invention include compounds having formula (V):
  • the compounds of the present invention include compounds having formula (VI):
  • the compounds of the present invention include compounds having formula (VII):
  • the compounds of the present invention include compounds having formula (VIII):
  • the compounds of the present invention include compounds having formula (IX):
  • the compounds of the present invention include compounds having formula (X):
  • the compounds of the present invention include compounds having formula
  • the compounds of the present invention include compounds having formula
  • the compounds of the present invention include compounds having formula
  • the compounds of the present invention include compounds having formula
  • the compounds of the present invention include compounds having formula
  • the compounds of the present invention include compounds having formula
  • the compounds of the present invention include compounds having formula (XVII):
  • the compounds of the present invention include compounds having formula (XVIII): Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs, isotopic isomers, and complexes thereof.
  • the compounds of the present invention include compounds having formula (XIX):
  • the compounds of the present invention include compounds having formula (XX):
  • X 1 is
  • X 1 is [0073] In some embodiments X 2 is N. [0074] In some embodiments X 2 is C. [0075] In some embodiments Z 1 is N. [0076] In some embodiments Z 1 is CR 1 . [0077] In some embodiments Z 2 is N. [0078] In some embodiments Z 2 is CR 4 . [0079] In some embodiments X 3 is CH 2 R. [0080] In some embodiments X 3 is -OR. [0081] In some embodiments X 3 is -NR3R.
  • X 3 is [0083] In some embodiments X 4 is CHR 5 [0084] In some embodiments X 4 is, O. [0085] In some embodiments X 4 is S. [0086] In some embodiments X 4 is SO. [0087] In some embodiments X 4 is SO2. [0088] In some embodiments X 5 is N. [0089] In some embodiments X 5 is C. [0090] In some embodiments X 6 is CR 7 . [0091] In some embodiments X 6 is NR 7 .
  • R is
  • R is
  • R is [0096] In some embodiments R is
  • n 1 is 1. [0099] In some embodiments n 1 is 2. [0100] In some embodiments n 1 is 3. [0101] In some embodiments n 1 is 4. [0102] In some embodiments n 1 is 5. [0103] In some embodiments n 1 is 6. [0104] In some embodiments n 1 is 7. [0105] In some embodiments n 1 is 8. [0106] In some embodiments n 1 is 9. [0107] In some embodiments n 1 is 10. [0108] In some embodiments n 1 is 11. [0109] In some embodiments n 1 is 12. [0110] In some embodiments n 1 is 13. [0111] In some embodiments n 1 is 14.
  • n 1 is 15. [0113] In some embodiments n 1 is 16. [0114] In some embodiments n 2 is 2. [0115] In some embodiments n 2 is 3. [0116] In some embodiments n 2 is 4. [0117] In some embodiments n 2 is 5. [0118] In some embodiments n 2 is 6. [0119] In some embodiments n 2 is 7. [0120] In some embodiments n 2 is 8.
  • n 3 is 1 [0122] In some embodiments n 3 is 2 [0123] In some embodiments n 3 is 3 [0124] In some embodiments n 3 is 4 [0125] In some embodiments n 3 is 5 [0126] In some embodiments n 3 is 6 [0127] In some embodiments n 3 is 7 [0128] In some embodiments n 3 is 8 [0129] In some embodiments n 4 is 1 [0130] In some embodiments n 4 is 2 [0131] In some embodiments n 4 is 3 [0132] In some embodiments n 4 is 4 [0133] In some embodiments n 4 is 5 [0134] In some embodiments n 4 is 6 [0135] In some embodiments n 4 is 7 [0136] In some embodiments n 5 is 1 [0137] In some embodiments n 5 is 2 [0138] In some embodiments n 5 is 3 [0139] In some embodiments n 5 is 4 [0140] In some embodiments
  • n 7 is 3.
  • n 7 is 4.
  • n 7 is 5.
  • n 7 is 6.
  • n 7 is 7.
  • n 8 is 1.
  • n 8 is 2.
  • n 8 is 3.
  • n 8 is 4.
  • n 8 is 5.
  • n 8 is 6.
  • n 8 is 7.
  • n 9 is 0.
  • n 9 is 1.
  • n 9 is 2.
  • n 9 is 3.
  • n 9 is 4.
  • n 9 is 5.
  • n 9 is 6.
  • n 9 is 7.
  • m 1 is 1.
  • m 1 is 2.
  • m 1 is 3.
  • m 2 is 0.
  • m 2 is 1.
  • m 2 is 2.
  • m 2 is 3.
  • R 1 is H. [0180] In some embodiments R 1 is halogen. [0181] In some embodiments R 1 is OH.
  • R 1 is CN
  • R 1 is C 1-6 alkyl.
  • R 1 is C 1-6 haloalkyl.
  • R 1 is C 3-7 branched alkyl. [0186] In some embodiments R 1 is C 3-7 cycloalkyl. [0187] In some embodiments R 1a is hydrogen.
  • R 1a is halogen
  • R 1a is C 1-6 alkyl.
  • R 1a is C 3-7 branched alkyl [0191] In some embodiments R 1a is C 3-7 cycloalkyl. [0192] In some embodiments R 1b is hydrogen.
  • R 1b is halogen
  • R 1b is C 1-6 alkyl.
  • R 1b is C 3-7 branched alkyl.
  • R 1c is C 3-7 cycloalkyl.
  • R 1c is hydrogen.
  • R 1c is halogen
  • R 1c is C 1-6 alkyl.
  • R 1c is C 3-7 branched alkyl. [0201] In some embodiments R 1c is C 3-7 cycloalkyl. [0202] In some embodiments R 1d is hydrogen.
  • R 1d is halogen
  • R 1d is C 1-6 alkyl.
  • R 1d is C 3-7 branched alkyl.
  • R 1d is C 3-7 cycloalkyl.
  • R 1e is hydrogen.
  • R 1e is halogen
  • R 1e is C 1-6 alkyl.
  • R 1e is C 3-7 branched alkyl. [0211] In some embodiments R 1e is C 3-7 cycloalkyl.
  • R 1f is hydrogen
  • R 1f is halogen
  • R 1f is C 1-6 alkyl.
  • R 1f is C 3-7 branched alkyl.
  • R 1f is C 3-7 cycloalkyl.
  • R 2 is H.
  • R 2 is halogen
  • R 2 is C 1-6 alkyl.
  • R 2 is C 1-6 haloalkyl.
  • R 2 is C3-7 branched alkyl.
  • R 2 is C 1-6 alkoxy.
  • R 2 is C 1-6 haloalkoxy.
  • R 2 is C 3-7 branched alkoxy.
  • R 2 is CN
  • R 2 is aromatic ring with 0-3 heteroatoms.
  • R 2 is C 3-7 cycloalkyl.
  • R 1 and R 2 are taken together to with the atoms to which they are bound to form a 5 membered ring that contains 0-2 heteroatoms.
  • R 1 and R 2 are taken together to with the atoms to which they are bound to form a 6 membered ring that contains 0-2 heteroatoms.
  • R 1 and R 2 are taken together to with the atoms to which they are bound to form a 7 membered ring that contains 0-2 heteroatoms.
  • R 3 is hydrogen
  • R 3 is C 1-6 alkyl.
  • R 3 is C 2-6 alkene.
  • R 4 is H.
  • R 4 is halogen
  • R 4 is C 1-6 alkyl.
  • R 4 is C 1-6 alkoxy. [0238] In some embodiments R 4 is CN.
  • R 3 and R 4 are taken together with the atoms to which they are bound to form a 5 membered ring with 0-2 heteroatoms.
  • R 3 and R 4 are taken together with the atoms to which they are bound to form a 6 membered ring with 0-2 heteroatoms.
  • R 3 and R 4 are taken together with the atoms to which they are bound to form a 7 membered ring with 0-2 heteroatoms.
  • R 3 and R 4 are taken together with the atoms to which they are bound to form a 5 membered aromatic ring with 0-2 heteroatoms.
  • R 3 and R 4 are taken together with the atoms to which they are bound to form a 6 membered aromatic ring with 0-2 heteroatoms.
  • R 5 is H.
  • R 5 is C 1-6 alkyl.
  • R 5 is C 3-7 branch alkyl.
  • R 6 is H.
  • R 6 is C 1-10 alkyl.
  • R 6 is C 1-10 haloalkyl.
  • R 6 is C 3-7 branched alkyl.
  • R 6 is C 3-7 cycloalkyl.
  • R 6 is optionally substituted aryl.
  • R 5 and R 6 are taken together to with the atoms to which they are bound to form a 5 membered ring.
  • R 5 and R 6 are taken together to with the atoms to which they are bound to form a 6 membered ring.
  • R 5 and R 6 are taken together to with the atoms to which they are bound to form a 7 membered ring.
  • R 7 is H.
  • R 7 is halogen
  • R 7 is C 1-6 alkyl.
  • R 7 is C 3-7 cycloalkyl. [0260] In some embodiments R 7 is C 3-7 branch alkyl.
  • R 7 is CN
  • R 8 is H.
  • R 8 is C 1-6 alkyl.
  • the compound having the formula has the chemical name (S)-9-((5-carboxypentyl)oxy)-6-isopropyl-10-methoxy-2-oxo- 6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid.
  • the compound having the formula has the chemical name (S)-9-(3-(carboxymethoxy)propoxy)-6-isopropyl-10-methoxy- 2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid.
  • a compound depicted by the racemic formula for example: will stand equally well for either of the two enantiomers having the formula: or the formula: or mixtures thereof, or in the case where a second chiral center is present, all diastereomers.
  • Exemplary embodiments include compounds having the formula (XXI) or a pharmaceutically acceptable salt form thereof: wherein non-limiting examples of X 3 .
  • Z 1 , Z 2 , R 2 , R 5 , R 6 , R 7 , and R 8 are defined herein below in Table 1:
  • Exemplary embodiments include compounds having the formula (XXII) or a pharmaceutically acceptable salt form thereof: wherein non-limiting examples of R, R 2 , R 5 , R 6 , R 7 , and R 8 are defined herein below in Table
  • Exemplary embodiments include compounds having the formula (XXIII) or a pharmaceutically acceptable salt form thereof: wherein non-limiting examples of X 3 , R 1 , R 5 , R 6 , R 7 , and R 8 are defined herein below in Table 3.
  • Exemplary embodiments include compounds having the formula (XXIV) or a pharmaceutically acceptable salt form thereof: wherein non-limiting examples of X 3 , R 2 , R 5 , R 6 , R 7 , and R 8 are defined herein below in Table 4.
  • Exemplary embodiments include compounds having the formula (XXVI) or a pharmaceutically acceptable salt form thereof: wherein non-limiting examples of X 3 , X 4 , Z 1 , Z 2 , R 2 , R 6 , R 7 , and R 8 are defined herein below in Table 4.
  • the present invention further relates to a process for preparing the compounds of the disclosure.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high pressure liquid chromatograpy (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).
  • HPLC high pressure liquid chromatograpy
  • GC gas chromatography
  • GPC gel-permeation chromatography
  • TLC thin layer chromatography
  • Preparation of the compounds can involve protection and deprotection of various chemical groups.
  • the need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated by reference herein for all purposes.
  • Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent’s freezing temperature to the solvent’s boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected.
  • the compounds of these teachings can be prepared by methods known in the art of organic chemistry.
  • the reagents used in the preparation of the compounds of these teachings can be either commercially obtained or can be prepared by standard procedures described in the literature.
  • compounds of the present invention can be prepared according to the method illustrated in the General Synthetic Schemes:
  • the reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature. In accordance with this invention, compounds in the genus may be produced by one of the following reaction schemes. [0280]
  • the first aspect of the process of the present invention relates to a process for preparing novel compounds of the disclosure having the formula (I). Compounds of formula (I) may be prepared according to the process outlined in Schemes 1-41.
  • a compound of the formula (1) a known compound or a compound prepared by known methods in which Y 1 is a C 1-6 alkyl
  • a compound of the formula (2) a known compound or compound prepared by known methods, in the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (3).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, triethylamine, diisopropylethylamine, pyridine, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chlor
  • a compound of the formula (3) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (4).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (4).
  • a compound of the formula (5) is reacted with a compound of the formula (6), a known compound or compound prepared by known methods, in the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (7).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, triethylamine, diisopropylethylamine, pyridine, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like
  • a compound of the formula (7) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (8).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (8).
  • a compound of the formula (9), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (10), a known compound or compound prepared by known methods in which Y 4 is selected from the group consisting of C 1-6 alkyl and tert-butyl, in the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (11).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, triethylamine, diisopropylethylamine, pyridine, and the like
  • a solvent such as tetrahydrofur
  • a compound of the formula (11) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (12).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (12).
  • a compound of the formula (11) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (12).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (12).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, triethylamine, diisopropylethylamine, pyridine, and the like
  • a solvent such as tetrahydro
  • a compound of the formula (15) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (16).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (16).
  • a compound of the formula (15) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (16).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (16).
  • a compound of the formula (17), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (18), a known compound or compound prepared by known methods in which Y 5 is selected from the group consisting of C 1-6 alkyl and tert-butyl, in the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (19).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, triethylamine, diisopropylethylamine, pyridine, and the like
  • a solvent such as tetrahydrofur
  • a compound of the formula (19) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (20).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (20).
  • a compound of the formula (19) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (20).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (20).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, triethylamine, diisopropylethylamine, pyridine, and the like
  • a solvent such as tetrahydr
  • a compound of the formula (23) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (24).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (24).
  • a compound of the formula (23) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (24).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (24).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, triethylamine, diisopropylethylamine, pyridine, and the like
  • a solvent such as tetrahydr
  • a compound of the formula (27) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (28).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (28).
  • a compound of the formula (27) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (28).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (28).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, triethylamine, diisopropylethylamine, pyridine, and the like
  • a solvent such as tetrahydrofur
  • a compound of the formula (31) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (32).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (32).
  • a compound of the formula (31) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (32).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (32).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, triethylamine, diisopropylethylamine, pyridine, and the like
  • a solvent such as tetrahydr
  • a compound of the formula (35) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (36).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (36).
  • a compound of the formula (35) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (36).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (36).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, triethylamine, diisopropylethylamine, pyridine, and the like
  • a solvent such as tetrahydr
  • a compound of the formula (39) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (40).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (40).
  • a compound of the formula (39) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (40).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (40).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, triethylamine, diisopropylethylamine, pyridine, and the like
  • a solvent such as tetrahydr
  • a compound of the formula (43) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (44).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (44).
  • a compound of the formula (43) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (44).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (44).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, triethylamine, diisopropylethylamine, pyridine, and the like
  • a solvent such as tetrahydr
  • a compound of the formula (47) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (48).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (48).
  • a compound of the formula (47) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (48).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (48).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, triethylamine, diisopropylethylamine, pyridine, and the like
  • a solvent such as tetrahydro
  • a compound of the formula (51) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (52).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (52).
  • a compound of the formula (51) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (52).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (52).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, triethylamine, diisopropylethylamine, pyridine, and the like
  • a solvent such as tetrahydr
  • a compound of the formula (55) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (56).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (56).
  • a compound of the formula (55) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (56).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (56).
  • a compound of the formula (59) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (60).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (60).
  • a compound of the formula (59) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (60).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (60).
  • a compound of the formula (63) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (64).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (64).
  • a compound of the formula (63) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (64).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (64).
  • a compound of the formula (65), a known compound or a compound prepared by known methods, is reacted with l-fluoro-4-methyl-l,4- diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) in the presence of a solvent such as ethanol, methanol, acetonitrile, dimethylformamide, dimethylacetamide, and the like,
  • a solvent such as ethanol, methanol, acetonitrile, dimethylformamide, dimethylacetamide, and the like
  • an acid such as acetic acid, trifluoroacetic acid, hydrochloric acid, and the like
  • a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, and the like optionally with heating, optionally with microwave irradiation to provide a compound of the formula (66).
  • a compound of the formula (67), a known compound or a compound prepared by known methods, is reacted with trichloroisocyanuric acid in the presence of a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (68).
  • a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, 1,4-dioxane, and the like
  • a compound of the formula (67) is reacted with N-chlorosuccinimide in the presence of a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (68).
  • a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (68).
  • a compound of the formula (71) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (72).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (72).
  • a solvent such as methylene chloride, tetrahydrofuran, 1,4- dioxane, dimethylformamide, and the like
  • a compound of the formula (78) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (79).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (79).
  • Y 4 is selected from the group consisting of C 1-6 alkyl and tert-butyl
  • a compound of the formula (83), a known compound or a compound prepared by known methods is reacted with a compound of the formula (84), a known compound or compound prepared by known methods in which Y 4 is selected from the group consisting of C 1-6 alkyl and tert-butyl, in the presence of zinc, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of an organophosphine such as 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2- dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclo
  • a compound of the formula (85) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (86).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (86).
  • a compound of the formula (85) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (86).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (86).
  • Y 4 is selected from the group consisting of C 1-6 alkyl and tert-butyl
  • compound of the formula (87), a known compound or a compound prepared by known methods is reacted with a compound of the formula (88), a known compound or compound prepared by known methods in which Y 4 is selected from the group consisting of C 1-6 alkyl and tert-butyl, in the presence of zinc, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of an organophosphine such as 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2- dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohex
  • a compound of the formula (89) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (90).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (90).
  • a compound of the formula (89) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (90).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (90).
  • Y 5 is selected from the group consisting of C 1-6 alkyl and tert-butyl
  • a compound of the formula (94), a known compound or a compound prepared by known methods is reacted with a compound of the formula (95), a known compound or compound prepared by known methods in which Y 5 is selected from the group consisting of C 1-6 alkyl and tert-butyl, in the presence of zinc, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of an organophosphine such as 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2- dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclo
  • a compound of the formula (96) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (97).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (97).
  • a compound of the formula (96) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (97).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (97).
  • Y 5 is selected from the group consisting of C 1-6 alkyl and tert-butyl
  • a compound of the formula (101) is reacted with a compound of the formula (102), a known compound or compound prepared by known methods in which Y 5 is selected from the group consisting of C 1-6 alkyl and tert-butyl, in the presence of zinc, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of an organophosphine such as 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-
  • a compound of the formula (103) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (104).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (104).
  • a compound of the formula (103) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (104).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (104).
  • Y 6 is selected from the group consisting of C 1-6 alkyl and tert-butyl
  • a compound of the formula (108), a known compound or a compound prepared by known methods is reacted with a compound of the formula (109), a known compound or compound prepared by known methods in which Y 6 is selected from the group consisting of C 1-6 alkyl and tert-butyl, in the presence of zinc, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of an organophosphine such as 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2- dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclo
  • a compound of the formula (110) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (111).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (111).
  • a compound of the formula (110) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (111).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (111).
  • a solvent such as methylene chloride, tetrahydrofuran, 1,4-dioxane, dimethylformamide, and the like
  • a compound of the formula (115), a known compound or a compound prepared by known methods is reacted with a compound of the formula (116), a known compound or compound prepared by known methods in which Y 6 is selected from the group consisting of C 1-6 alkyl and tert-butyl, in the presence of zinc, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of an organophosphine such as 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2- dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclo
  • a compound of the formula (117) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (118).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (118).
  • a compound of the formula (117) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (118).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4- dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (118).
  • a solvent such as methylene chloride, tetrahydrofuran, 1,4-dioxane, dimethylformamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (124).
  • a compound of the formula (122) is reacted with a compound of the formula (123), a known compound or compound prepared by known methods in which Y 7 is selected from the group consisting of C 1-6 alkyl and tert-butyl, in the presence of zinc, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of an organophosphine such as 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-
  • a compound of the formula (124) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (125).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (125).
  • a compound of the formula (124) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (125).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (125).
  • Y 7 is selected from the group consisting of C 1-6 alkyl and tert-butyl
  • a compound of the formula (129) is reacted with a compound of the formula (130), a known compound or compound prepared by known methods in which Y 7 is selected from the group consisting of C 1-6 alkyl and tert-butyl, in the presence of zinc, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of an organophosphine such as 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-
  • a compound of the formula (131) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (132).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (132).
  • a compound of the formula (131) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (132).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (132).
  • a compound of the formula (133) is reacted with a compound of the formula (134), a known compound or compound prepared by known methods in which Y 7 is selected from the group consisting of C 1-6 alkyl and tert-butyl, in the presence of zinc, in the presence of sodium iodide, in the presence of nickel(II) iodide, in the presence of 1,10-phenanthroline, optionally in the presence of a base such as pyridine, triethylamine, diisopropylethylamine, and the like, in the presence of a solvent such as methylene chloride, tetrahydrofuran, 1,4- dioxane, dimethylformamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (135).
  • a compound of the formula (134) a known compound or compound prepared by known methods in which Y 7 is selected from the group consisting of C 1-6 alkyl and tert-but
  • a solvent such as methylene chloride, tetrahydrofuran, 1,4-dioxane, dimethylformamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (138).
  • a compound of the formula (136) is reacted with a compound of the formula (137), a known compound or compound prepared by known methods in which Y 8 is selected from the group consisting of C 1-6 alkyl and tert-butyl, in the presence of zinc, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of an organophosphine such as 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-
  • a compound of the formula (138) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (139).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (139).
  • a compound of the formula (138) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (139).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (139).
  • a compound of the formula (140) is reacted with a compound of the formula (141), a known compound or compound prepared by known methods in which Y 8 is selected from the group consisting of C 1-6 alkyl and tert-butyl and Q 1 is selected from the group consisting of halogen and (halogen) 2 Li, optionally in the presence of sodium iodide, optionally in the presence of nickel(II) iodide, optionally in the presence of 1,10- phenanthroline, optionally in the presence of a palladium catalyst such as a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, optionally in the presence of a base such as pyridine, triethylamine
  • a compound of the formula (143) is reacted with a compound of the formula (144), a known compound or compound prepared by known methods in which Y 8 is selected from the group consisting of C 1-6 alkyl and tert-butyl, in the presence of zinc, in the presence of sodium iodide, in the presence of nickel(II) iodide, in the presence of 1,10-phenanthroline, in the presence of a solvent such as methylene chloride, tetrahydrofuran, 1,4-dioxane, dimethylformamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (145).
  • a solvent such as methylene chloride, tetrahydrofuran, 1,4-dioxane, dimethylformamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (145).
  • a compound of the formula (143) is reacted with a compound of the formula (144), a known compound or compound prepared by known methods in which Y 8 is selected from the group consisting of C 1-6 alkyl and tert-butyl, in the presence of zinc, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of an organophosphine such as 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-
  • a compound of the formula (145) is reacted with a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (146).
  • a base such as sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (146).
  • a compound of the formula (145) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (146).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as tetrahydrofuran, 1,4-dioxane, dimethylformamide, methylene chloride, dichloroethane, methanol, ethanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (146).
  • a compound of the formula (147) is reacted with a compound of the formula (148), a known compound or compound prepared by known methods in which Y 8 is selected from the group consisting of C 1-6 alkyl and tert-butyl and Q 1 is selected from the group consisting of halogen and (halogen) 2 Li, optionally in the presence of sodium iodide, optionally in the presence of nickel(II) iodide, optionally in the presence of 1,10- phenanthroline, optionally in the presence of a palladium catalyst such as a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, optionally in the presence of a base such as pyridine, triethylamine
  • Mobile phase flow was 1.0 mL/min with a 3.0 min gradient from 20% aqueous media (0.1% formic acid) to 95% CH 3 CN (0.1% formic acid) and a 9.0 min total acquisition time.
  • Silica gel column chromatography was performed using Teledyne ISCO silica gel columns (20-40 microns or 40-60 microns), and the eluent was a mixture of ethyl acetate and hexanes, or mixture of methanol and ethyl acetate.
  • HPLC high-performance liquid chromatography
  • Examples 1-8 provides methods for preparing representative compounds of formula (I). The skilled practitioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare additional compounds of the present invention.
  • Example 1 Synthesis of (S)-9-(carboxymethoxy)-6-isopropyl-10-methoxy-2- oxo-6, 7-dihydro-2H-pyrido [2,1-a]isoquinoline-3-carboxylic acid (65042-A-OH): (S)-ethyl 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3- carboxylate (15 mg, 0.0420 mmol) and potassium carbonate (17 mg, 0.126 mmol) was dissolved in 2 mL N,N-dimethylformamide.
  • 3-carboxylic acid was prepared according to the procedure of example 1, except that (S)- ethyl 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline- 3-carboxylate was replaced with (S)-ethyl 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6,7- dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate and methyl 2-bromoacetate was replaced with methyl 4-bromobutanoate.
  • Example 3 Synthesis of (S)-9-(4-carboxybutoxy)-6-isopropyl-10-methoxy-2- oxo-6, 7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (65042-D-OH): (S)-9-(4- carboxybutoxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3- carboxylic acid was prepared according to the procedure of example 1, except that (S)-ethyl 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3- carboxylate was replaced with (S)-ethyl 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6,7- dihydro-2H-pyr
  • Example 4 Synthesis of (S)-9-((5-carboxypentyl)oxy)-6-isopropyl-10- methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (65025-B-OH): (S)-9-((5-carboxypentyl)oxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,l- a]isoquinoline-3-carboxylic acid was prepared according to the procedure of example 1, except that (S)-ethyl 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1- a]isoquinoline-3-carboxylate was replaced with (S)-ethyl 9-hydroxy-6-isopropyl-10- methoxy-2-
  • Example 5 Synthesis of (S)-9-(3-(carboxymethoxy)propoxy)-6-isopropyl-10- methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (65025-C-OH): (S)-9-(3-(carboxymethoxy)propoxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H- pyrido[2,1-a]isoquinoline-3-carboxylic acid was prepared according to the procedure of example 1, except that (S)-ethyl 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H- pyrido[2,1-a]isoquinoline-3-carboxylate was replaced with (S)-ethyl 9-hydroxy-6-isopropyl- 10-methoxy-2-
  • Example 6 Synthesis of (S)-9-((6-carboxyhexyl)oxy)-6-isopropyl-10- methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (65042-E-OH): (S)-9-((6-carboxyhexyl)oxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1- a]isoquinoline-3-carboxylic acid was prepared according to the procedure of example 1, except that (S)-ethyl 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1- a]isoquinoline-3-carboxylate was replaced with (S)-ethyl 9-hydroxy-6-isopropyl-10- methoxy-2-
  • Example 7 Synthesis of (S)-9-((7-carboxyheptyl)oxy)-6-isopropyl-10- methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (65063-A-OH): (S)-9-((7-carboxyheptyl)oxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1- a]isoquinoline-3-carboxylic acid was prepared according to the procedure of example 1, except that (S)-ethyl 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1- a]isoquinoline-3-carboxylate was replaced with (S)-ethyl 9-hydroxy-6-isopropyl-10- methoxy-2-
  • Example 8 Synthesis of (S)-9-((8-carboxyoctyl)oxy)-6-isopropyl-10- methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (65063-B-OH): (S)-9-((8-carboxyoctyl)oxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1- a]isoquinoline-3-carboxylic acid was prepared according to the procedure of example 1, except that (S)-ethyl 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1- a]isoquinoline-3-carboxylate was replaced with (S)-ethyl 9-hydroxy-6-isopropyl-10- methoxy
  • the present invention also relates to compositions or formulations which comprise the hepatoselective Polyadenylating Polymerases 5 and 7 (PAPD 5 & 7) inhibitors according to the present invention.
  • the compositions of the present invention comprise an effective amount of one or more of the compounds of the disclosure and salts thereof according to the present invention which are effective for treating or preventing diseases that involve Polyadenylating Polymerases 5 and 7 activity such as hepatitis B and liver cancer; and one or more excipients.
  • excipient and “carrier” are used interchangeably throughout the description of the present invention and said terms are defined herein as, “ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition.”
  • excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient.
  • An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach.
  • the formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.
  • compositions that include at least one compound described herein and one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • pharmaceutically acceptable carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington's Pharmaceutical Sciences , 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985), the entire disclosure of which is incorporated by reference herein for all purposes.
  • pharmaceutically acceptable refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient.
  • pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
  • Compounds of the present teachings can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers.
  • Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials.
  • the compounds can be formulated in conventional manner, for example, in a manner similar to that used for known hepatitis therapies and cancer therapies.
  • Oral formulations containing a compound disclosed herein can comprise any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions.
  • the carrier in powders, can be a finely divided solid, which is an admixture with a finely divided compound.
  • a compound disclosed herein in tablets, can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets can contain up to 99 % of the compound.
  • Capsules can contain mixtures of one or more compound(s) disclosed herein with inert filler(s) and/or diluent(s) such as pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.
  • inert filler(s) and/or diluent(s) such as pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.
  • Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins.
  • pharmaceutically acceptable diluents including
  • Surface modifying agents include nonionic and anionic surface modifying agents.
  • Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine.
  • Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the compound(s).
  • the oral formulation can also consist of administering a compound disclosed herein in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.
  • Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, elixirs, and for inhaled delivery.
  • a compound of the present teachings can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, or a pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators.
  • liquid carriers for oral and parenteral administration include, but are not limited to, water (particularly containing additives as described herein, e.g., cellulose derivatives such as a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil).
  • the carrier can be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellants.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • Compositions for oral administration can be in either liquid or solid form.
  • the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the pharmaceutical composition can be sub-divided in unit dose(s) containing appropriate quantities of the compound.
  • the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • Such unit dosage form can contain from about 1 mg/kg of compound to about 500 mg/kg of compound, and can be given in a single dose or in two or more doses.
  • Such doses can be administered in any manner useful in directing the compound(s) to the recipient’s bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally.
  • an effective dosage can vary depending upon the particular compound utilized, the mode of administration, and severity of the condition being treated, as well as the various physical factors related to the individual being treated.
  • a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications.
  • the dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician.
  • the variables involved include the specific condition and its state as well as the size, age and response pattern of the patient.
  • a compound directly to the airways of the patient, using devices such as, but not limited to, metered dose inhalers, breath-operated inhalers, multidose dry-powder inhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers.
  • devices such as, but not limited to, metered dose inhalers, breath-operated inhalers, multidose dry-powder inhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers.
  • the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition.
  • the liquid composition can include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, a pump or a squeeze-actuated nebulized spray dispenser.
  • the solvents can be, for example, isotonic saline or bacteriostatic water.
  • the solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present teachings intermixed with lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation.
  • the aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellants, surfactants, and co-solvents, and can be administered by, for example, a metered device.
  • the propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellants that are physiologically and environmentally acceptable.
  • compositions described herein can be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or a pharmaceutically acceptable salts, hydrates, or esters thereof can be prepared in water suitably mixed with a surfactant such as hydroxyl-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms.
  • the pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form can sterile and its viscosity permits it to flow through a syringe.
  • the form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Compounds described herein can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts, hydrates, or esters thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
  • Transdermal administration can be accomplished through the use of a transdermal patch containing a compound, such as a compound disclosed herein, and a carrier that can be inert to the compound, can be non-toxic to the skin, and can allow delivery of the compound for systemic absorption into the blood stream via the skin.
  • the carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
  • the creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in- water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the compound can also be suitable.
  • occlusive devices can be used to release the compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the compound with or without a carrier, or a matrix containing the compound.
  • Other occlusive devices are known in the literature.
  • Compounds described herein can be administered rectally or vaginally in the form of a conventional suppository.
  • Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository’s melting point, and glycerin.
  • Water-soluble suppository bases such as polyethylene glycols of various molecular weights, can also be used.
  • Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.
  • a compound can be combined with other agents effective in the treatment of the target disease.
  • other active compounds i.e., other active ingredients or agents
  • the other agents can be administered at the same time or at different times than the compounds disclosed herein.
  • Compounds of the present teachings can be useful for the treatment or inhibition of a pathological condition or disorder in a mammal, for example, a human subject.
  • the present teachings accordingly provide methods of treating or inhibiting a pathological condition or disorder by providing to a mammal a compound of the present teachings including its pharmaceutically acceptable salt) or a pharmaceutical composition that includes one or more compounds of the present teachings in combination or association with pharmaceutically acceptable carriers.
  • Compounds of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment or inhibition of the pathological condition or disorder.
  • compositions according to the present invention include from about 0.001 mg to about 1000 mg of one or more compounds of the disclosure according to the present invention and one or more excipients; from about 0.01 mg to about 100 mg of one or more compounds of the disclosure according to the present invention and one or more excipients; and from about 0.1 mg to about 10 mg of one or more compounds of the disclosure according to the present invention; and one or more excipients.
  • PAPD 5/7 Biochemical assay PAPD5 (accession #: NM_001040285) and PAPD7 (accession #: NM_0069999) open reading frames were recombined into Flag-tagged pCDNA3.1 vectors to make plasmids pCMV-FlagD5 and pCMV-FlagD7, respectively.
  • HEK293 cells grown in 10 cm dishes were then transiently transfected with 5 ug pCMV- FlagD5 or pCMV-FlagD7.
  • RNA oligonucleotides Two days post the transfection, cell lysates were prepared (Cell Signaling Cat#: 9803S) and tagged PAPD5 and PAPD7 polypeptides were precipitated with M2 anti-Flag antibody (Sigma Cat#: A2220).
  • PAPD5 or PAP7 bound on agarose beads were directly utilized for polyadenylating reaction in 10 ul buffer containing 10 mM Tris-HCl (pH 8.0), 100 mM KC1, 3.2 mM MgCl 2 , 1mM ATP and 100 nM P32-labeled RNA oligonucleotides (5'- GCCUUUC AU CUCU A ACU GC G A A A A A A A A A A A -3') ⁇ The polyadenylating reactions of RNA oligonucleotides were carried out at 37°C for 20 minutes and 3 hours for the PAPD5 and PAPD7 polypeptides, respectively.
  • the reaction was terminated by the addition of an equal volume of 2X RNA loading buffer (NEB, Cat#: B0363S).
  • a 2.5 ul fraction of tail-elongated product was resolved in 15% Urea-Tris-Borate- EDTA (Urea-TBE) gel (Themofisher Cat#: EC6865BOX), and the radioactive signals were scanned with a Typhoon Phosphorimager.
  • Cellular assays method 1 Cellular assays: The HBV producing cell line HepG2.2.15 was cultured in DMEM/F12 containing 10% fetal bovine serum (FBS), 100 U/ml penicillin and 100 ⁇ g/ml streptomycin (Invitrogen). Compounds of the disclosure in DMSO was added into the culture medium when cell reached 100% confluence. The final concentration of DMSO was adjusted to 0.5%. Culture medium was replaced in two days and the cell was cultured for additional two days in the presence of compound. HBsAg inhibition in culture medium was then detected with AlphaLisa assay using anti-HBsAg antibodies of 10-H05H and 60C-CR2100RB from Fitzgerald Intemantional.
  • Cellular assays method 2 HepG2.2.15 cells were seeded in duplicate into white, 96-well plates at 1.5 x 104 cells/well. The cells were treated with a 3-fold serial dilution series of the compounds in DMSO. The final DMSO concentration in all wells was 1%, and DMSO was used as no drug control.
  • the HBsAg chemiluminescence immunoassay (CLIA) kit Autobio Diagnostics Co., Zhengzhou, China was used to measure the levels of secreted HBV antigens semi-quantitatively. For the detection, 50 ⁇ L/well culture supernatant was used and the procedure conducted as directed by manufacturer's instructions.
  • the cytotoxicity was measured using CellTiter-Glo (Promega, Madison, WI, USA, catalogue no. G7571). Dose-response curves were generated and the IC 50 and CC 50 values were calculated using Graphpad prism.
  • the IC 50 and CC 50 are defined as the compound concentration (or conditioned media log dilution) at which HBsAg secrection and cytotoxicity, respectively, are reduced by 50% compared to the no drug control.
  • Compounds of the disclosure can also be assessed to determine their utility for as PAPD 5 and 7 inhibitors using the methods described in W02017016960, WO2019123285, W02020106816A1, WO2018022282, WO2017216685, and
  • Protocol for pharmacokinetic and tissue distribution studies The pharmacokinetics of the compounds was studied in CD1 mice after intravenous (IV) and oral gavage (PO) administration. Mouse PK studies was conducted at 3 mg/kg (IV) and 8 mg/kg (PO). Plasma samples obtained from dosed animals, at ten time points, including 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8 and 24 hr post-dose for processing to plasma, were prepared for analysis by means of a single step protein precipitation technique, by adding 200 ⁇ L of acetonitrile containing an IS mixture (labetalol, imipramine and diclofenac) to 50 pL aliquots of individual subject samples.
  • an IS mixture labeletalol, imipramine and diclofenac
  • Table 7 and 8 provide pharmacokinetic data and calculated PK properties after a 3 mg/kg IV administration of 65042-E-OH (Example 6) to CD1 mice.
  • Tables 9 and 10 provide pharmacokinetic data and calculated PK properties after an 8 mg/kg oral administration of 65042-E-OH (Example 6) to CD1 mice.
  • Table 11 provides a comparison of plasma concentration to liver concentration in CD1 mice after oral administration of 8 mg/kg of 65042-E-OH (Example 6) to CD1 mice.
  • the results in 7 through 11 demonstrate the surprising and unexpected result that compounds of the disclosure are taken up by the liver, a feature not observed in previous generations of PAPD 5 and 7 inhibitors.
  • Table 7 PK data for 3mg/kg IV dose of 65042-E-OH (Example 6) in CD1 mice
  • Table 8 Calculated PK parameters of 3 mg/kg IV dose of 65042-E-OH (Example 6) in CD1 mice
  • Table 9 PK data for 8 mg/kg oral dose of 65042-E-OH (Example 6) in CD1 mice.
  • Table 10 Calculated PK parameters of 8 mg/kg oral dose of 65042-E-OH (Example 6) in CD1 mice
  • Table 11 Comparison of liver and plasma concentration of 65042-E-OH (Example 6) in CD1 mice after 8 mg/kg oral dose of 65042-E-OH (Example 6)
  • Transfected HEK293 and vector control HEK293 cells were cultured in 24-well poly-D-lysine or collagen-coated tissue culture plates (as appropriate) and treated with a test compound at two concentrations (0.5 and 5 ⁇ M) for 2 and 10 minutes respectively in transport buffer (HBSSg, pH 7.4, pre-warmed to 37°C).
  • transport buffer HBSSg, pH 7.4, pre-warmed to 37°C.
  • the uptake experiments were stopped by removing dosing solution followed by two washes of ice-cold HBSSg buffer. The cells were lysed for 2 minutes with 75% ACN containing an appropriate internal standard (when available).
  • Lysis buffer were chilled to - 20°C, and the plate was kept on ice during lysis.
  • the cell lysate was transferred into a 96- well plate for sample analysis with LC-MS/MS analysis to determine concentration of test compound in cell lysate.
  • the uptake of test compounds was normalized by total cell protein using the BCA Protein Assay Kit following the manufacturer’s protocol.
  • the inhibitor Rifamycin SV was used to block OATP1B1 and OATP1B3 transporter activity in order to determine uptake ratios.
  • Results of OATP1B1 and OATP1B3 transporter studies for exemplary compounds of the disclosure, DHQ-1, and the positive control Estradiol 17- ⁇ Glucuronide are shown in table 12 and table 13.
  • Data for compounds of the disclosure and the positive control tested using Mock cells are also shown in tables 12 and 13.
  • the results in tables 12 and 13 demonstrate the surprising and unexpected result that compounds of the disclosure are substrates for the OATP1B1 and OATP1B3 transporters, a feature not observed in previous generations of PAPD 5 and 7 inhibitors.
  • Table 12 Data from OATP1B1 transporter activity of compounds of the disclosure using in
  • Mock cells are normal HEK293.
  • Table 13 Data from OATP1B3 transporter activity of compounds of the disclosure using in

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